Irritable-hostile depression: further validation as a bipolar depressive mixed state

BACKGROUND: "Hostile depression" has unofficially long been described as a depressive subtype, but since DSM-III, the affect has been made a defining characteristic of borderline personality disorder. The related affect of irritability in DSM-IV-TR subsumes various hostile nuances and is included in the stem question for mood disorders--especially for hypomanic episodes; in children, it is nonetheless a sign of depression. Then, there is the unofficial more general concept of depression with anger attacks, until recently ostensibly a "unipolar" (UP) disorder. A veritable tower of Babel indeed. In the present analyses, our aim was to extend previous research on irritable-hostile depression to more specific parameters of bipolarity and depressive mixed state (DMX). METHODS: Consecutive 348 bipolar-II (BP-II) and 254 unipolar (UP) major depressive disorder (MDD) outpatients (off psychoactive agents, including substances of abuse), were interviewed with the Structured Clinical Interview for DSM-IV, the Hypomania Interview Guide, and the Family History Screen. Borderline personality, a confounding variable, rare in the FB setting, was excluded. Irritability was defined according to DSM-IV-TR, which includes various features of hostility and anger. Depressive mixed state (DMX) was defined as a major depressive episode (MDE) plus three or more concurrent intradepressive hypomanic symptoms, whether it occurred in BP-II or MDD. RESULTS: MDE with irritability was present in 59.7% (208/348) of BP-II and in 37.4% (95/254) of MDD (p=0.0000). In BP-II, MDE with, versus MDE without, irritability had significantly younger index age, higher rates of axis I comorbidity, atypical depressive features, and DMX. Upon logistic regression, we found a significant independent association between BP-II MDE with irritability and DMX. In UP, MDE with, versus without, irritability had significantly younger age and age at onset, higher rates of atypical depression, DMX, and bipolar family history. Logistic regression revealed a significant independent association between MDE with irritability and DMX. Given that we had excluded patients with borderline personality, the high prevalence of irritable-hostile depressives in this outpatient population means that hostility cannot be considered the signature of that personality. Factor analysis revealed independent "psychomotor activation" and "irritability-mental activation" factors. Odds ratios of irritability for DMX were highest in the "UP" MDD group (=12.2); for predicting DMX, irritability had the best psychometric profile of sensitivity of 66.3% and a specificity of 86.1% for this group as well. LIMITATION: We did not use specific instruments to measure irritable, hostile, and angry affects. CONCLUSIONS: These analyses show that irritable-hostile depression is distinct from agitated depression. Whether arising from a BP-II or MDD baseline, irritable-hostile depression emerges as a valid entity with strong links to external bipolar validators, such as bipolar family history. Irritable-hostile phenomenology in depression appears to be a strong clinical marker for a DMX. Irritable-hostile depression as a variant of DMX deserves the benefit of what seems to work best in practice, i.e., anticonvulsant mood stabilizers and/or atypical antipsychotics. Formal treatment studies are very much needed.     

Diagnostic depressive symptoms of the mixed bipolar episode

BACKGROUND: There is not yet consensus on the best diagnostic definition of mixed bipolar episodes. Many have suggested the DSM-III-R/-IV definition is too rigid. We propose alternative criteria using data from a large patient cohort. METHODS: We evaluated 237 manic in-patients using DSM-III-R criteria and the Scale for Manic States (SMS). A bimodally distributed factor of dysphoric mood has been reported from the SMS data. We used both the factor and the DSM-III-R classifications to identify candidate depressive symptoms and then developed three candidate depressive symptom sets. Using ROC analysis we determined the optimal threshold number of symptoms in each set and compared the three ROC solutions. The optimal solution was tested against the DSM-III-R classification for crossvalidation. RESULTS: The optimal ROC solution was a set, derived from both the DSM-III-R and the SMS, and the optimal threshold for diagnosis was two or more symptoms. Applying this set iteratively to the DSM-III-R classification produced the identical ROC solution. The prevalence of mixed episodes in the cohort was 13.9% by DSM-III-R, 20.2% by the dysphoria factor and 27.4% by the new ROC solution. CONCLUSIONS: A diagnostic set of six dysphoric symptoms (depressed mood, anhedonia, guilt, suicide, fatigue and anxiety), with a threshold of two symptoms, is proposed for a mixed episode. This new definition has a foundation in clinical data, in the proved diagnostic performance of the qualifying symptoms, and in ROC validation against two previous definitions that each have face validity.     

Evaluating the inter-episode stability of depressive mixed states

BACKGROUND: Depressive mixed state (DMX) is understudied, although this diagnostic concept may be of clinical and theoretical importance. Our goal was to provide preliminary evidence of the inter-episode stability of DMX. The inter-episode stability is known to be an important validator for establishing a distinct clinical entity. METHODS: Out of depressive patients consecutively hospitalized at our institute, those who experienced two or more hospitalizations due to discrete depressive recurrences during a 6-year period were selected. All depressive episodes were directly observed and assessed using a standardized rating instrument in terms of eight intra-episode manic symptoms (flight of idea, logorrhea, aggression, excessive social contact, increased drive, irritability, racing thoughts, and distractibility). Assessments for subsequent episodes were performed blindly to those for previous episodes within each patient. RESULTS: The inter-episode stability of categorical DMX diagnoses and the number of intra-episode manic symptoms was moderate but significantly high. Approximately 50% of patients with DMX in the index episode obtained a DMX diagnosis in the second episode. Approximately 40% of the total variance of the number of intra-episode manic symptoms was explained by agreements across several depressive episodes. Depressive patients who experienced a diagnostic switch from unipolar to bipolar disorder had a higher frequency of DMX and a greater number of intra-episode manic symptoms in the index as well as subsequent episodes. LIMITATIONS: All consecutive patients were not followed up. Bipolar I and II patients were combined due to a small number of bipolar II patients in this sample. CONCLUSION: The inter-episode stability of DMX may not be so high as is required for establishing a distinct clinical entity. However, the findings strongly suggest that some depressive patients have a long-lasting liability to DMX. It is important to determine whether such a liability to DMX is mediated by affective temperaments, as was originally hypothesized by Akiskal [J. Clin. Psychopharmacol. 16 (1996) 4S-14S]. DMX may be a risk factor to the diagnostic switch from unipolar to bipolar disorder.     

Clinical subtypes of severe bipolar mixed states

Objective

The aim of the present study was to identify different clinical subtypes in severe, treatment resistant bipolar mixed state (MS).

Method

The sample comprised 202 Bipolar I patients currently in MS referred for an Electro-convulsive Therapy (ECT) trial and evaluated in the first week of hospitalization and one week after the ECT course. Principal component factor analysis (PCA) followed by Varimax rotation was performed on 21 non-overlapping items selected from Hamilton rating-scale for depression (HAMD) and from Young mania rating-scale (YMRS) at baseline evaluation. Cluster subtypes derived from the factor scores were compared in clinical variables and final HAMD, YMRS, Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression (CGI) scores.

Results

The principal-component analysis extracted 6 interpretable factors explaining 55.9% of the total variance. Cluster analysis identified four groups, including respectively 63 (31.2%) subjects with Agitated-Irritable Mixed-Depression, 59 (29.2%) with Psychotic Mixed-Mania, 17 (8.5%) with Anxious-Irritable-Psychotic Mixed-Mania, and 63 (31.2%) with Retarded-Psychotic Mixed-Depression. The four clusters were statistically distinct and did not show significant overlap in the main symptomatological presentation. Cluster subtypes reported differences in number of past mood episodes, duration of the current episode, suicide attempts, lifetime comorbidity with panic and eating disorders, baseline and final rating-scale scores and rate of remission after ECT trial.

Conclusions

Our study indicates that, at least in severe treatment resistant MS, multiple depressive and manic subtypes can be observed with substantial differences in terms of clinical presentation, course, associated comorbidities and treatment response.     

High rate of unrecognized bipolar mixed states among destitute Hispanic adolescents referred for "major depressive disorder"

OBJECTIVE: To ascertain the rate of bipolarity among adolescent Hispanic youths referred for the treatment of "major depressive disorder" (MDD) in a community mental health clinic (CMHC) in which the threshold for referral was moderate to severe impairment. METHODS: The patients were 49 consecutively presenting Hispanic adolescents (33 girls and 16 boys with a range of 12-17 years), many of whom had histories of unruly, hostile and/or assaultive behavior; indeed, 1 out of 3 had been referred to the CMHC from the "First-Time Offenders Program." Upon evaluation at the CMHC triage unit, all were diagnosed as MDD rendered by a licensed paramedical mental health professional managing this unit. They were subsequently evaluated by a psychiatrist using the Structured Clinical Interview for DSM-IV. RESULTS: Seventeen (51.5%) of the girls and 10 (62.5%) of the boys met the DSM-IV criteria for bipolar disorder. Among the bipolars, 44.4% were bipolar II and 55.6% bipolar I; 74.1%% had mixed states and 40.7% were psychotic (not mutually exclusive categories). Euphoric mania was virtually absent in this population. LIMITATION: Data on social deviance was based on chart review. Nonetheless, given that a third had already entered the juvenile justice system upon referral validates the accuracy of characterizing this population as at least moderately impaired from the social deviance standpoint. CONCLUSIONS: Hispanic adolescents referred with a presumptive diagnosis of MDD must be carefully assessed for the presence of occult bipolarity using a structured interview. Concurrent aggressiveness and depression should tip mental health clinicians towards bipolarity--especially mixed states. Such activated-hostile depressive (and/or manic) mixed states may in part underlie the social deviance in these patients. Given that these destitute youth are often simultaneously encountered in the juvenile justice system, undetected bipolarity among Hispanic adolescents initially regarded to have MDD represents a matter of grave public health importance. Appropriate training for mental health staff to recognize bipolar spectrum disorders in CMHCs should be mandated.     

Distinct seasonality of depressive episodes differentiates unipolar depressive patients with and without depressive mixed states

BACKGROUND: The bipolar nature of unipolar depression with depressive mixed states (DMX) needs further validation studies. The seasonality of depressive episodes is indicated to be different between unipolar and bipolar depressions. We therefore explored the seasonal pattern of depressive episodes in unipolar depressive patients with DMX. METHODS: The subjects were 958 consecutive depressive inpatients for a 6-year period. For defining DMX, previously validated operational criteria were used (2 or more of 8 manic or mania-related symptoms: flight of idea, logorrhea, aggression, excessive social contact, increased drive, irritability, racing thoughts, and distractibility). Onsets of the index depressive episodes during each of the 12 calendar months were summed up over the 6-year for bipolar depressive patients (N = 95), and unipolar depressive patients with (N = 77) and without DMX (N = 786) separately. An appropriate statistic was used for testing seasonality. RESULTS: A significant seasonal variation with a large peak in spring was recognized in unipolar depression without DMX, while both bipolar depression and unipolar depression with DMX had a significant fall peak. The monthly distribution of depressive episodes was significantly different between unipolar depression without DMX and other 2 diagnostic categories. Similar results were obtained in separate analyses for each gender. LIMITATIONS: Further replication study using an epidemiological or outpatient sample is needed. Bipolar I and II patients were combined due to a small number of bipolar II patients in this sample. CONCLUSION: Unipolar depression with DMX has a seasonal pattern similar to bipolar depression. The finding provides further evidence of the bipolar nature of unipolar depression with DMX.     

Gender, suicidality and bipolar mixed states in adolescents

BACKGROUND: The purpose of this study was to determine the relationship between mixed states and suicidality among adolescent outpatients presenting with a DSM-IV defined major depressive episode (MDE). METHODS: Two-hundred and forty-seven adolescents meeting the criteria for MDE were screened for the presence of concurrent, intra-MDE hypomania/mania (i.e., mixed states). All patients were asked whether they had current suicidal ideation or had recently attempted any self-destructive physical act associated with the thought of dying (i.e., a suicide attempt). The data were subjected to analysis using univariate logistic regression. RESULTS: One hundred of the 247 (40.5%) adolescents were bipolar type I or type II. Of these, 82% were in mixed states. Of the patients with suicidal ideation, 62.8% were girls, and of those with histories of a suicide attempt, 69.4% were girls. Girls had more than twice the risk of having suicidal ideation (OR=2.2, p=0.004) and nearly 3 times the risk of having histories of a suicide attempt than boys (OR=2.87, p<0.0001). Being in a mixed state per se did not predict either suicidal ideation or a suicide attempt among all of the 247 patients. However, mixed states apparently independently contributed to the risk of (non-fatal) suicidal behavior among girls only. Of the mixed states, girls had nearly 4 times the risk of having made a suicide attempt compared with those without mixed states (OR=3.9, p=0.003). Age, presence of psychotic features and family history of mood disorder had little or no bearing on suicidality. LIMITATIONS: Correlational chart review study, no data collection on Axis I and Axis II comorbidity and adverse life-events. CONCLUSIONS: This report of greater suicidality in adolescent girls in a mixed state parallels the well-known adult literature of high frequency of mixed states in women. The findings are of relevance to the controversy of antidepressants and suicidality in juvenile depressives in that they identify a vulnerable group. In line with earlier suggestions by the senior author [Akiskal, H.S., 1995. Developmental pathways to bipolarity: are juvenile-onset depressions pre-bipolar? J. Am. Acad. Child Adolesc. Psych. 34, 754-763], our data highlight the public health importance of the wider recognition of bipolar mixed states in juvenile patients masquerading as unipolar depression. Finally, it appears to us that it is the failure of our formal nosology on mixed states--rather than the antidepressants per se--which is the root problem in this controversy.     

Delineating bipolar II mixed states in the Ravenna-San Diego collaborative study: the relative prevalence and diagnostic significance of hypomanic features during major depressive episodes

BACKGROUND: Depressive mixed state (DMX), defined by hypomanic features during a major depressive episode (MDE) is under-researched. Accordingly, study aims were to find DMX prevalence in unipolar major depressive disorder (MDD) and bipolar II depressive phase, to delineate the most common hypomanic signs and symptoms during DMX, and to assess their sensitivity and specificity for the diagnosis of DMX and bipolar II. METHODS: 161 unipolar and bipolar II MDE psychotropic drug- and substance-free consecutive outpatients were interviewed during an MDE with the Structured Clinical Interview for DSM-IV. DMX was defined at two threshold levels as an MDE with two or more (DMX2), and with three or more (DMX3) simultaneous intra-episode hypomanic signs and symptoms. RESULTS: DMX2 was present in 73.1% of bipolar II, and in 42.1% of unipolar MDD (P<0.000); DMX3 was present in 46.3% of bipolar II, and in 7.8% of unipolar MDD (P<0.000). The most common hypomanic manifestations during MDE were irritability, distractibility, and racing thoughts. Irritability had the best combination of sensitivity and specificity for the diagnosis of DMX2 and DMX3. Various combinations of irritability, distractibility, and racing thoughts correctly classified the highest number of DMX2 and DMX3, and had the strongest predictive power. DMX2 had high sensitivity and low specificity for bipolar II, whereas DMX3 had low sensitivity (46.3%) and high specificity (92.1%). LIMITATIONS: Single interviewer, cross-sectional assessment, and interviewing clinician not blind to patients' unipolar vs. bipolar status. CONCLUSIONS: When conservatively defined (>or = 3 intra-episode hypomanic signs and symptoms during MDE), DMX is prevalent in the natural history of bipolar II but uncommon in unipolar MDD. These findings have treatment implications, because of growing concerns that antidepressants may worsen DMX, which in turn may respond better to mood stabilizers. These data also have methodological implications for diagnostic practice: rather than solely depending on the vagaries of the patient's memory for past hypomanic episodes, the search for hypomanic features--ostensibly elation would not be one of those--during an index depressive episode could enhance the detection of bipolar II in otherwise pseudo-unipolar patients. Strict adherence to current clinical diagnostic interview instruments (e.g. the SCID) would make such detection difficult, if not impossible.     

Oxcarbazepine as add-on treatment in patients with bipolar manic, mixed or depressive episode

OBJECTIVES: The aim of this preliminary open-label trial was to evaluate the efficacy and safety of oxcarbazepine (OXC) as adjunctive therapy in 18 patients with bipolar disorder who did not respond satisfactorily to lithium. METHODS: Eighteen patients with bipolar I (n=16) and bipolar II (n=2) disorder were treated openly with OXC for a 8-week period as add-on treatment to the existing lithium regimen. After the 8-week trial, all patients continued the treatment with OXC, and were followed-up prospectively. Outcome measures included the Clinical Global Impression-Bipolar Version Scale, the Bech-Rafaelsen Mania-Melancholia Scale and the Brief Psychiatric Rating Scale. These scales were administered at baseline and at the end of weeks 2, 4 and 8. Patients were subsequently assessed every 4 months for a period of time ranging from 4 to 12 months with the Longitudinal Interval Follow-up Evaluation. RESULTS: The mean dose of OXC at the end of week 8 was 919.4 mg/day (SD+/-335.7). Eleven of the 18 patients were considered responders. The remaining seven patients were rated as nonresponders. Of the eleven responders to the 8-week trial, seven patients remained mood-stabilized for the entire period of follow-up. CONCLUSIONS: OXC appeared to be significantly effective as add-on strategy in 60% of patients after 8 weeks of treatment. A substantial proportion (66.3%) of the 8-week trial responders maintained a satisfactory mood stabilization during the follow-up. Despite several limitations, our study suggests the potential usefulness of OXC as adjunctive therapy to lithium both in acute and long-term treatment of bipolar disorder.     

The nature of the depressive symptomatology preceding myocardial infarction

Little is known about the nature of the depressive symptomatology preceding myocardial infarction (MI). Specification of the depressive symptomatology is important for the development of hypotheses about the biological mechanisms relating depressive symptoms to MI. To test the hypothesis that feelings of fatigue and loss of energy have the strongest predictive power of all depressive symptoms, the authors reanalyzed data from a prospective study of 3877 healthy men aged 40 to 65 years. The men's mental state was assessed using the Maastricht Questionnaire, a scale that measures vital exhaustion, which is characterized by unusual fatigue and lack of energy, increased irritability, and depressive symptoms, including demoralization. Oblique factor analysis was used to validate these dimensions. Results of Cox's regression analyses showed that the fatigue subscale has the strongest predictive power for incident MI and that depression and irritability subscales lose their predictive power when controlled for fatigue.     

Family functioning and mood disorders: a comparison between patients with major depressive disorder and bipolar I disorder

Within a sample of patients with major depressive disorder (MDD; n = 121) and bipolar affective disorder (BPAD; n = 69), the authors examined (a) diagnostic differences in family functioning at acute episode, (b) diagnostic differences in family functioning at episode recovery, (c) within-group changes in family functioning from acute episode to recovery, and (d) whether within-group changes from acute episode to recovery varied by diagnosis. Using a multidimensional model, the authors evaluated interviewer, patient, and family ratings. Overall, patients with MDD and BPAD evidenced similar levels of family impairment at acute episode and recovery. Generally, patients in both groups experienced improvement in family functioning over time, yet mean scores at recovery continued to range from fair to poor. Although certain specific differences emerged, diagnostic groups appeared to be more similar than different in level and pattern of family functioning.     

Family history influences age of onset in bipolar I disorder in females but not in males.

Age of onset (AO) has been proposed as a promising criterion by which to select homogeneous subgroups for the genetic analysis of bipolar disorder. This is the first study to investigate the effect of the interaction between gender and family history (FH)-type on AO in bipolar disorder. In accordance with the literature, no difference in AO was observed between females and males in our sample of 264 Romanian bipolar I probands. Cox regression, however, showed a strong influence of FH-type on AO (P = 0.006). This was due to a significant variation in AO according to the type of FH in females (P = 0.002) but not in males (P = 0.64). Female bipolar disorder patients with a negative FH (FH(-)) had a later AO than females with either a FH of bipolar and/or schizoaffective disorder (P = 0.001) or a FH of recurrent unipolar major depression only (P = 0.04). Females with FH(-) had a later AO than males with FH(-) (P = 0.03). No sex difference was observed for AO in the group with a FH of recurrent unipolar depression. In the group with a FH of bipolar and/or schizoaffective disorder, females had an earlier AO than males (P = 0.01). A trend for support was observed in an independent sample of 217 German bipolar I patients for an influence of FH-type on AO in females (P = 0.09) but not in males (P = 0.15). Female bipolar disorder patients with FH(-) had a later AO than females with either a FH of bipolar and/or schizoaffective disorder (P = 0.04) or a FH of recurrent unipolar major depression only (P = 0.05). Females with FH(-) had a later AO than males with FH(-) (P = 0.05). Other comparisons were statistically not significant, which may be due to limited sample size. Our findings emphasize that the interaction between gender and FH-type is a source of heterogeneity for AO in bipolar disorder.     

Family history of psychiatric disorder and low self-confidence: predictors of depressive symptoms at 12-month follow-up.

We examined effects of two risk factors for depression, family psychiatric history and Low Self-Confidence, on (1) baseline characteristics of major depression and (2) depressive symptoms one year later. Subjects (N = 104) in the midst of a depressive episode were assigned to one of three family history subtypes identified in earlier research: Pure Depressive Disease (PDD) Depressive Spectrum Disease (DSD), Sporadic Depressive Disease (SDD). Results indicate that effects of Self-Confidence on depressive symptoms at follow-up varied by family subtype. In multivariate analyses with controls for demographic and illness characteristics, the mean follow-up depressive score was below the depressive threshold for PDD subjects and above it for SDD subjects regardless of the level of Self-Confidence. In contrast, DSD subjects with High Self-Confidence reported significantly more symptoms than those with Low Self-Confidence.